Undiagnosed diseases take a disproportionate toll on the health care system and on affected patients and families. Our renewal application builds on our success in helping to form and grow the current Undiagnosed Diseases Network (UDN). Our proposal strengthens a collaborative network of researchers and healthcare providers, all with a stake in improving healthcare and outcomes for persons affected by various rare genetic disorders. Our approach synergizes basic and clinical research and patient care with the use of cutting-edge phenotyping technologies, an array of world class experts, and the translation of genome sequencing to the bedside. This results in a greatly improved diagnostic process for rare genetic diseases and facilitates novel discovery in clinical practice. Investigating rare diseases involving multiple systems and incorporating comprehensive genomic data into clinical care creates considerable challenges, from the interpretation of vast amounts of genetic variants to their relevance to the symptoms, to the communication issues linked to their disclosure, and to their impact on clinical management. Our proposal describes our current UDN Clinical Site and modifications necessary to transition to a sustainable clinic model that functions within the UCLA Health System and as a component of an ongoing international network to tackle the incorporation of cutting edge molecular diagnostics into the clinical workflow, analyze patients? symptoms in a standardized and reproducible fashion, and perform research investigations to elucidate the mechanisms of undiagnosed diseases. We will reach these overarching goals by implementing the following specific aims: Aim 1: Sustain a UDN clinic model that functions locally and network-wide; Aim 2: Investigate the clinical phenotypes of new and rare disorders; Aim 3: Investigate the underlying mechanisms of new and rare disorders; Aim 4: Build a network-wide sustainable infrastructure for translational research on new and rare disorders. Substantial David Geffen School of Medicine resources are available to facilitate the transition and maintenance of the sustainable clinic model that serves an essential need with the UCLA Health System, the School of Medicine, and the Institute for Precision Health. The UCLA approach is an efficient model for accelerating translational and clinical research while improving care delivery and augmenting the educational mission of UCLA. Our project integrates the resources of (1) the infrastructure of the UCLA Clinical and Translational Science Institute, (2) an experienced team of clinicians from all specialty fields, (3) expertise in the combined interrogation of DNA and RNA sequencing data for novel gene discovery; (4) expertise in the investigation of environmental effects on clinical symptoms; (5) expertise in outcomes of genetic counseling and testing, (6) access to a large, ethnically varied population and (7) a sustainable approach that includes training clinicians, genetic counselors, and basic scientists in the multidisciplinary approach to solve undiagnosed diseases.